title: Netting neutrophils are major inducers of type I IFN production in pediatric systemic lupus erythematosus.
abstract: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by a breakdown of tolerance to nuclear antigens and the development of immune complexes. Genomic approaches have shown that human SLE leukocytes homogeneously express type I interferon (IFN)-induced and neutrophil-related transcripts. Increased production and/or bioavailability of IFN-α and associated alterations in dendritic cell (DC) homeostasis have been linked to lupus pathogenesis. Although neutrophils have long been shown to be associated with lupus, their potential role in disease pathogenesis remains elusive. Here, we show that mature SLE neutrophils are primed in vivo by type I IFN and die upon exposure to SLE-derived anti-ribonucleoprotein antibodies, releasing neutrophil extracellular traps (NETs). SLE NETs contain DNA as well as large amounts of LL37 and HMGB1, neutrophil proteins that facilitate the uptake and recognition of mammalian DNA by plasmacytoid DCs (pDCs). Indeed, SLE NETs activate pDCs to produce high levels of IFN-α in a DNA- and TLR9 (Toll-like receptor 9)-dependent manner. Our results reveal an unsuspected role for neutrophils in SLE pathogenesis and identify a novel link between nucleic acid-recognizing antibodies and type I IFN production in this disease.
authors.affiliation: Baylor Institute for Immunology Research, Dallas, TX 752014, USA.
authors.forename: Gina S
authors.initials: GS
authors.lastname: Garcia-Romo
authors.forename: Simone
authors.initials: S
authors.lastname: Caielli
authors.forename: Barbara
authors.initials: B
authors.lastname: Vega
authors.forename: John
authors.initials: J
authors.lastname: Connolly
authors.forename: Florence
authors.initials: F
authors.lastname: Allantaz
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Xu
authors.forename: Marilynn
authors.initials: M
authors.lastname: Punaro
authors.forename: Jeanine
authors.initials: J
authors.lastname: Baisch
authors.forename: Cristiana
authors.initials: C
authors.lastname: Guiducci
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coffman
authors.forename: Franck J
authors.initials: FJ
authors.lastname: Barrat
authors.forename: Jacques
authors.initials: J
authors.lastname: Banchereau
authors.forename: Virginia
authors.initials: V
authors.lastname: Pascual
mesh_terms: D000293:Adolescent; D000974:Antibodies, Antinuclear / Q000097:blood; D017209:Apoptosis / Q000276:immunology; D001323:Autoantibodies / Q000097:blood; D016022:Case-Control Studies; D002648:Child; D003713:Dendritic Cells / Q000276:immunology; D020869:Gene Expression Profiling; D006801:Humans; D007370:Interferon Type I / Q000096:biosynthesis*; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000235:genetics / Q000276:immunology*; D009249:NADP / Q000097:blood; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis; D017452:Receptors, IgG / Q000097:blood; D012261:Ribonucleoproteins / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000097:blood
chemical_list: D000974:Antibodies, Antinuclear; D001323:Autoantibodies; C080568:Fc gamma receptor IIA; D007370:Interferon Type I; D017452:Receptors, IgG; D012261:Ribonucleoproteins; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D009249:NADP